1. Field of Invention
Appetite and weight control or reduction in human patients; long-term treatment without the development of tolerance; employment of femoxetine and salts thereof in such method, particularly such method involving treatment of obese human patients over a period of at least eight (8) weeks.
2. Prior Art
Over the past years, numerous agents have been employed or proposed for their anorexigenic and weight control or reduction effects, particularly in obese humans. These agents have been of numerous types. Sympathomimetic amines have been employed but generally have been found to have the objectionable side effects of anxiety, restlessness, and insomnia due to their strong central nervous system stimulatory effect. Compounds of other structures have therefore been explored. Among the compounds proposed for anorexigenic drugs for the control or reduction of appetite and weight are compounds which increase the neuronal release of noradrenaline (NA) and dopamine (DA). Such compounds have been found effective, but are subject to the disadvantages that patients generally develop a tolerance to such drugs as are currently available. As a result, extended treatment is not feasible, since the anorexigenic effect tends to diminish by the eighth week of administration or earlier, with resulting termination of weight reduction and, in fact, a return to a weight gain situation from previously attained low levels despite continuation of treatment beyond the point where tolerance develops. The potential use of such products has accordingly been severely curtailed in practice, since appetite and weight control and reduction programs, especially in obese patients, are most desirably continued far beyond an eight-week treatment schedule. Of available anorexigenic drugs, only fenfluramine has appeared to have an anorexigenic and weight-reducing effect over a treatment period extending beyond eight (8) weeks. Fenfluramine is, however, recognized as being characterized by a mode of action which is different from the serotonin (5-HT) uptake-inhibitors, in fact operating by the stimulation of the release of 5-HT from storage sites rather than by blocking its uptake, so that no conclusions can be reached with regard to 5-HT uptake-inhibitors or blockers based upon the performance of the known 5-HT release-stimulating drug fenfluramine. Since fenfluramine is also releasing NA and DA, the effect on 5-HT is not selective.
Numerous efforts to provide long-acting anorexigenic drugs, to which the patient does not develop tolerance, of various types and structures, have been undertaken, but with no substantial elimination of their shortcomings. The need for additional and improved products and long-term methods for the effective control and reduction of appetite and weight, especially in obese patients, without undesirable side effects, is apparent.
The possible use of 5-HT uptake-inhibitors in modifying feeding behavior and decreasing food intake in rats is reviewed by J. E. Blundell in the "International Journal of Obesity" (1977), 1, at pages 15-42. A copy of this publication will be provided upon filing the present application. Blundell and Latham expanded the art in this field with their article entitled "Pharmacological Manipulation of Feeding Behavior: Possible Influences of Serotonin and Dopamine on Food Intake" in the book entitled Central Mechanisms of Anorectic Drugs, edited by S. Garattini and R. Samanin, Raven Press, New York (1978) at pages 83-109, a copy of which will also be provided. At pages 89 and 90, figures evidencing the effect of anorectic drugs on eating behavior as measured during a one-hour feeding test are provided, including the product FG 4963, which is the product femoxetine, as its hydrochloride. These authors did not suggest that femoxetine would be a valuable anorectic drug over a long-term period, much less for a period in excess of eight (8) weeks, without evidence of patient-developed tolerance or untoward side effects, or even that femoxetine would have anorectic action beyond the one-hour eating period involved in the test protocol they reported.
Of course, it is already well-established that a single dose of an anorectic drug can result in a loss of appetite and weight, but that food intake and weight quickly return to base line and are followed by overeating and weight gain with an ultimate result of excess food intake, overeating, and increase in body fat which can persist as long as two (2) months or more. This is established, for example, for amphetamine, "the prototypical drug for producing anorexia and weight loss in animals and people", Hoebel et al., Princeton University, Life Sciences Vol. 28, pp. 77-82 (1981), Pergamon Press.
Among anorectic drugs which do produce patient-developed tolerance after eight (8) weeks of treatment or earlier and which, accordingly, are not of value in such treatment beyond that point, may be mentioned the products diethylpropion, chlorphentermine, phentermine, desamphetamine, and phenmetrazine, as set forth in the review article in "Drugs", 1975, 10(4), pages 241-328, and as graphically illustrated in FIG. 3, page 271 of that article.
In the use of femoxetine as a prophylactic treatment for migraine, with treatment extending at a 400 mg daily dosage over a period of six (6) weeks, an observed side effect was reduced appetite and weight loss, but there was no suggestion that tolerance would not appear or had not appeared from the anorectic standpoint and there was no indication that such tolerance would not appear in treatment schedules extending over eight (8) weeks and beyond. Some of our results with femoxetine were also noted in a publication in "Alimentazione Metabolismo Nutrizione" (1980), 1, 383, an abstract of a paper presented at the Third International Congress on Obesity in Rome, Oct. 8-11, 1980, which was published as early as June, 1980 but which was not further elaborated upon at the conference or followed by any expanded publication. This publication is within one year of the date on which the present application will be filed.
Other publications relating to femoxetine as a potential thymoleptic include the "European Journal of Pharmacology", 32 (1975) 108-115 and "Psychopharmacologia" (Berl.) 42, 21-26 (1975), which do not mention anorexigenic activity. Finally, the basic U.S. patent covering femoxetine is U.S. Pat. No. 3,912,743, issued Oct. 14, 1975, which discloses use of femoxetine and related compounds as anti-depressant and anti-Parkinson agents.